Team:Duesseldorf/Apoptosis
Apoptosis
Apoptosis is an active process of cell death, which is essential for homeostasis and development of metazoan organisms. For instance it is necessary for the regeneration of the intestinal epithelium, the metamorphosis of frogs and the formation of toes and fingers in embryogenesis in mammals.
In contrast to necrosis it is a regulated process, which neither results in acute cell injury nor leads to an inflammation of tissue, because of leaking cell content. The process of apoptosis is controlled by enzymes, called caspases. In the course of the process, cell fragments called apoptotic bodies are produced. They contain fragmented DNA and cell organelles.
Furthermore, the membrane phospholipid phosphatidylserine (PS), which is normally localized in the inner monolayer of the cell membrane and is vital for intracellular transduction pathways or exocytosis, is flipped to the outer monolayer in apoptosis. This so called “eat-me-signals” recruit macrophages, which then conduct phagocytosis of the apoptotic cell.[1]
There are two different ways to induce apoptosis. The first one is the extrinsic pathway, triggered through extracellular stimuli like the Fas ligand on killer lymphocytes, which binds to a Fas receptor on the target cell. This signal leads to activation of Caspase 8 and 10 and finally to apoptosis. [2]
The second way to induce apoptosis is the intrinsic pathway. Initially this pathway is triggered by DNA damage. Pathways that are activated in response to these damages finally leads to release of cytochrome c, which normally is required in respiration. Cytochrome c is located only within the mitochondrial intermembrane-space, and streams out during apoptosis. [3]
Our project focuses on the intrinsic pathway, more precisely on the release of cytochrome c from the intermembrane-space through the outer mitochondrial membrane (OMM), which is the consequence of the activation of Bcl-2 family proteins. Proapoptotic members of this family such as Bax and Bak, are able to form pores in lipid bilayers. Cytochrome c is able to pass through these pores in the OMM.
Cytochrome c activates a cytosolic protein called Apaf-1, which has an N-terminal CAR domain (caspase recruitment domain). This CAR domain induces the self-cleavage/activation of caspase-9 through heterodimerization. This complex is called the apoptosome and leads to activation of a cascade of caspases inducing apoptosis. [4]
References :
[1]=J Biol Chem. 1997 Oct 17;272(42):26159-65.
Appearance of phosphatidylserine on apoptotic cells requires calcium-mediated nonspecific flip-flop and is enhanced by loss of the aminophospholipid translocase.
Bratton DL1, Fadok VA, Richter DA, Kailey JM, Guthrie LA, Henson PM.
[2]=FEBS Letters 1995-10-16
Interaction of peptides derived from the Fas ligand with the Fyn-SH3 domain.
M Hane, B Lowin, M Peitsch, K Becker, J Tschopp
[3]=Annu Rev Biochem. 2004;73:87-106.
Cytochrome C-mediated apoptosis.
Jiang X1, Wang X.
[4]=Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria? November 1998 Yoshihide Tsujimoto
